We examine the contributions of individual genes to the genetic determination of complex behavioral traits. Because brain serotonin pathways regulate many mammalian physiological and behavioral phenomena, our primary focus is on gene products that contribute to this signaling system. To shed light on the mechanisms through which serotonin regulates neurobehavioral processes such as anxiety/fear responses, ingestive behavior and reward, we use molecular genetic procedures to generate lines of mice with null mutations (constitutive, region-specific and inducible) of serotonin receptor genes. Detailed behavioral analyses of the impact of these mutations are pursued, revealing abnormalities that provide a focus for multidisciplinary studies of the neural mechanisms underlying the regulation of complex behaviors.
In view of the widespread use of serotonergic drugs such as Prozac for the treatment of conditions such as anxiety and depression, we have an interest in examining the serotonergic regulation of such processes. Mice bearing a null mutation of the 5-HT1A receptor represent a useful model for this work. These "hyperserotonergic" animals lack the predominant inhibitory autoreceptor of serotonergic neurons, resulting in elevated extracellular serotonin levels. Animals lacking 5-HT1A receptors display enhanced anxiety-like responses in a variety of behavioral assays and a robust antidepressant-like responses in an animal model of depression. We are examining neural mechanisms through which serotonin system hyperactivity produces these abnormalities of behavior.
We are also interested in the serotonergic regulation of ingestive behavior. We have observed an eating disorder in animals bearing null mutations of the serotonin 5-HT2C receptor subtype. These animals overeat and develop a late onset ("middle-age" obesity) syndrome associated with physiological changes characteristic of human obesities. To examine the neural basis of this disorder, we are developing sophisticated ethologically-based behavioral assays to dissect the neuropsychological processes that govern ingestive behavior in mice. Such studies are performed in conjunction with neuroanatomical, genetic and pharmacological approaches to examine neural mechanisms through which 5-HT2C receptors regulate feeding.
In addition to their role in the regulation of food ingestion, increasing attention is being paid to the influences of brain serotonin systems on the ingestion of abused drugs. The rewarding properties of abused drugs and natural reinforcers appear to share common neural pathways that are regulated by serotonin. In accord with this, we have uncovered abnormal responses of 5-HT2C and 5-HT6 receptor mutant mice to drugs such as psychostimulant and alcohol. These responses provide a focus for our efforts to examine neural mechanisms through which serotonin systems influence brain reward pathways.